Hereditary hemochromatosis is a genetic disorder that promotes increased intestinal absorption and progressive tissue deposition of iron resulting in cirrhosis of the liver, hepatic carcinoma, congestive heart failure, endocrinopathies and premature death. It is estimated that 1 in 200-to-400 people in the US are homozygous for this disease which is the most common defective genetic trait known in humans, more prevalent than cystic fibrosis, phenylketonuria and muscular dystrophy combined. Iron assimilation is a tightly regulated process that is limited to prevent harmful effects due to overload of this toxic metal and therefore a reciprocal relationship exists between body iron stores and dietary iron absorption, although the molecular basis for ion homeostasis remains unknown. Many studies of the molecular basis for hemochromatosis have evaluated the expression of factors involved in iron metabolism , including transferrin, transferrin receptor, ferritin and IRPs, but strong evidence to support their abnormal regulation in this disease is lacking. We recently identified SFT (Stimulator of Fe Transport) as a facilitator of non-transferrin-bound iron uptake. Our preliminary results demonstrate that SFT expression is down- regulated at both the mRNA and protein level in response to iron-loading. However, in the course of these studies, we made the significant discovery that SFT mRNA is 5-fold higher in liver from hemochromatosis patients despite the deposition of iron that occurs in this tissue. Thus, our working hypothesis is that malregulated expression of SFT contributes to the etiology of hemochromatosis. The proposed research will specifically evaluate our hypothesis through the following goals: 1) determination of SFT activity in iron transport by hepatocytes and intestinal enterocytes; 2) examination of interactions of interactions with the hemochromatosis protein Hfe that may modulate SFT expression and function in these cells; and 3) characterization of the mechanism that regulates SFT expression.